Reversible modification of proteins with linkage-specific ubiquitin chains is critical for intracellular signaling. Information on physiological roles and underlying mechanisms of particular ubiquitin linkages during human development are limited. Here, relying on genomic constraint scores, we identify 10 patients with multiple congenital anomalies caused by hemizygous variants in OTUD5, encoding a K48/K63 linkage–specific deubiquitylase. By studying these mutations, we find that OTUD5 controls neuroectodermal differentiation through cleaving K48-linked ubiquitin chains to counteract degradation of select chromatin regulators (e.g., ARID1A/B, histone deacetylase 2, and HCF1), mutations of which underlie diseases that exhibit phenotypic overlap with OTUD5 patients. Loss of OTUD5 during differentiation leads to less accessible chromatin at neuroectodermal enhancers and aberrant gene expression. Our study describes a previously unidentified disorder we name LINKED (LINKage-specific deubiquitylation deficiency–induced Embryonic Defects) syndrome and reveals linkage-specific ubiquitin cleavage from chromatin remodelers as an essential signaling mode that coordinates chromatin remodeling during embryogenesis.

Peroxisome Proliferator Activated Receptor Gamma Co-activator-1 (PGC-1) is a well-conserved protein among all chordates. Entire Drosophila species subgroup carries a PGC-1 homolog in their genome called spargel/dPGC-1 showing very little divergence. Recent studies have reported that significant functional similarities are shared between vertebrate and invertebrate PGC-1's based on their role in mitochondrial functions and biogenesis, gluconeogenesis, and most likely in transcription and RNA processing. With the help of genetic epistasis analysis, we established that Drosophila Spargel/dPGC-1 affects cell growth process as a terminal effector in the Insulin-TOR signaling pathway. The association between Spargel/dPGC-1 and Insulin signaling could also explain its role in the aging process. Here we provided a further comparison between Spargel/dPGC-1 and PGC-1 focusing on nuclear localization, oxidative stress resistance, and a possible role of Spargel/dPGC-1 in oogenesis reminiscing the role of Spargel in reproductive aging like many Insulin signaling partners. This led us to hypothesize that the discovery of newer biological functions in Drosophila Spargel/dPGC-1 will pave the way to uncover novel functional equivalents in mammals.

Metazoan development from a one-cell zygote to a fully formed organism requires complex cellular differentiation and communication pathways. To coordinate these processes, embryos frequently encode signaling information with the small protein modifier ubiquitin, which is typically attached to lysine residues within substrates. During ubiquitin signaling, a three-step enzymatic cascade modifies specific substrates with topologically unique ubiquitin modifications, which mediate changes in the substrate’s stability, activity, localization, or interacting proteins. Ubiquitin signaling is critically regulated by deubiquitylases (DUBs), a class of ~100 human enzymes that oppose the conjugation of ubiquitin. DUBs control many essential cellular functions and various aspects of human physiology and development. Recent genetic studies have identified mutations in several DUBs that cause developmental disorders. Here we review principles controlling DUB activity and substrate recruitment that allow these enzymes to regulate ubiquitin signaling during development. We summarize key mechanisms of how DUBs control embryonic and postnatal differentiation processes, highlight developmental disorders that are caused by mutations in particular DUB members, and describe our current understanding of how these mutations disrupt development. Finally, we discuss how emerging tools from human disease genetics will enable the identification and study of novel congenital disease-causing DUBs.